An EGFR inhibitor intermediate and its synthesis method and application

Abstract

The present invention discloses an EGFR inhibitor intermediate and its synthesis method and application. It relates to the field of drug synthesis technology. The above-mentioned EGFR inhibitor intermediate comprises the following structure: wherein R1, R3 and R4 are independently selected from an alkyl group with a carbon number of 1-8 or its derivatives. The EGFR inhibitor intermediate is used to synthesize EGFR inhibitors, which are targeted drugs for treating lung cancer or other cancers. In addition, the method of the present invention has few synthesis steps, a simple process and is easy to operate. The entire process does not use expensive and dangerous compounds, especially does not use sodium hydrogen compounds, does not use palladium carbon catalysts, and does not use palladium carbon hydrogenation synthesis methods, so that the method of the present invention has no safety risks.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to an EGFR inhibitor intermediate and a synthesis method and application thereof. Background Art

[0002] EGFR inhibitors are targeted drugs currently used to treat lung cancer and other cancers. Marketed EGFR inhibitors are categorized into first, second, and third generations. All three generations of EGFR inhibitors can develop varying degrees of resistance in patients. To address this resistance, the development of new EGFR inhibitors is urgently needed. 5-Isopropyl-8-methoxy-9-nitro-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepane and its derivatives are key intermediates in the synthesis of a new class of EGFR inhibitors.

[0003] However, the current synthesis of 5-isopropyl-8-methoxy-9-nitro-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepane and its derivatives requires many steps, and the synthesis process uses a large number of expensive catalysts and some dangerous chemical reagents, resulting in a high cost of the API for this type of EGFR inhibitor. Specifically, the existing synthesis steps for 5-isopropyl-8-methoxy-9-nitro-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepane are as follows:

[0004]

[0005] Obviously, the entire synthetic route is a long one, with 9 steps of reaction from the starting materials to 6A-5. The starting materials are expensive. An expensive palladium-carbon catalyst is used in the synthesis of intermediate 1C-2, and the reaction uses a relatively dangerous palladium-carbon hydrogenation method. The synthesis of 6A-2 is a Suzuki coupling reaction, which requires the use of precious metal palladium as a catalyst. The dangerous compound sodium hydrogen is used in the synthesis of 6A-5.

[0006] Based on this, it is very important to develop a method for synthesizing 5-isopropyl-8-methoxy-9-nitro-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepane and its derivatives with high yield and high purity. Summary of the Invention

[0007] The first technical problem to be solved by the present invention is:

[0008] Provided is an EGFR inhibitor intermediate.

[0009] The second technical problem to be solved by the present invention is:

[0010] Provided is a method for synthesizing the EGFR inhibitor intermediate.

[0011] The third technical problem to be solved by the present invention is:

[0012] Application of the EGFR inhibitor intermediate.

[0013] In order to solve the first technical problem, the technical solution adopted by the present invention is:

[0014] An EGFR inhibitor intermediate comprising the following structure:

[0015]

[0016] Wherein, R1, R3 and R4 are independently selected from an alkyl group having 1 to 8 carbon atoms or a derivative thereof.

[0017] According to an embodiment of the present invention, R1, R3 and R4 are independently selected from an alkyl group having 1 to 3 carbon atoms or a derivative thereof.

[0018] In order to solve the second technical problem, the technical solution adopted by the present invention is:

[0019] A method for synthesizing the EGFR inhibitor intermediate comprises the following steps:

[0020] S1 uses compound 0 as the starting material and reacts to obtain compound 1;

[0021] S2 Compound 1 reacts with Compound A to obtain Compound 2;

[0022] S3 reacts with compound 2 under catalytic conditions to produce compound 3;

[0023] S4: Compound 3 is mixed with a bromine-containing compound and reacted to obtain an EGFR inhibitor intermediate;

[0024] Among them, the structural formula of compound 0 is:

[0025] Among them, the structural formula of compound 1 is:

[0026] Wherein, the structural formula of compound A is:

[0027] Among them, the structural formula of compound 2 is:

[0028] Among them, the structural formula of compound 3 is:

[0029] Wherein, R2 is one of -Br and -I.

[0030] According to the embodiments of the present invention, one of the technical solutions has at least one of the following advantages or beneficial effects:

[0031] 1. The existing synthesis method requires 9 steps to obtain the target product, while the method of the present invention only requires 4 steps to obtain the same target product. The method of the present invention has fewer synthesis steps, a simple process and is easy to operate. The entire process does not use dangerous compounds, especially no sodium hydrogen compounds, no palladium carbon catalysts, and no palladium carbon hydrogenation synthesis method, so that the method of the present invention has no safety risks.

[0032] 2. The method of the present invention uses readily available starting materials, has low cost, ensures good reproducibility of the synthetic route, and is a process that can be scaled up for production.

[0033] According to an embodiment of the present invention, R2 is one of -Br and -I, but it cannot be determined that R2 cannot be a halogen group other than -Br and -I. The selection of R2 should be based on the experimenter's specific requirements for the performance of the EGFR inhibitor and / or the specific requirements for the yield of the synthesized EGFR inhibitor.

[0034] According to an embodiment of the present invention, the halogen group refers to a group containing F, Cl, Br or I.

[0035] According to an embodiment of the present invention, the method for synthesizing the EGFR inhibitor intermediate is as follows:

[0036] Among them, compound 4 is an EGFR inhibitor intermediate.

[0037] According to one embodiment of the present invention, the process of generating compound 1 by reacting compound 0 further includes the following raw materials: a lithium-containing compound, N-formylmorpholine and methoxymethyltriphenylphosphine chloride.

[0038] According to one embodiment of the present invention, the lithium-containing compound includes at least one of n-butyllithium, n-propyllithium and n-ethyllithium.

[0039] According to one embodiment of the present invention, in step S3, the catalytic conditions include performing a catalytic reaction using tris(dibenzylideneacetone)dipalladium as a catalyst.

[0040] According to one embodiment of the present invention, the catalytic reaction has a reaction temperature of 80-90° C. and a reaction time of 10-16 hours.

[0041] According to one embodiment of the present invention, the reaction temperature of the catalytic reaction is selected from any one of the following temperatures or a temperature range consisting of any two temperatures: 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 98°C and 90°C.

[0042] According to one embodiment of the present invention, the reaction time of the catalytic reaction is selected from any one of the following time periods or an interval consisting of any two of the following time periods: 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours and hours.

[0043] According to one embodiment of the present invention, step S4 includes the following steps: mixing compound 3 with a bromine-containing compound under alkaline conditions.

[0044] According to one embodiment of the present invention, the bromine-containing compound includes isopropyl bromide.

[0045] According to one embodiment of the present invention, during the mixing of compound 3 and the bromine-containing compound, the temperature is controlled at 0-10°C during mixing, and after mixing, the temperature is raised to 20-30°C for reaction.

[0046] According to one embodiment of the present invention, during the process of mixing compound 3 with the bromine-containing compound, the choice of temperature during the mixing and temperature control can be determined based on actual conditions.

[0047] According to one embodiment of the present invention, during the mixing process of compound 3 and the bromine-containing compound, the temperature during the mixing is selected from the following temperature range consisting of any one or any two temperatures: 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C and 10°C.

[0048] According to one embodiment of the present invention, in the process of mixing compound 3 with the bromine-containing compound, the temperature is controlled at 0-10°C during mixing. After mixing, the temperature is raised to any one of the following temperatures or a temperature range consisting of any two temperatures for reaction: 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C and 30°C.

[0049] Another aspect of the present invention relates to the use of the EGFR inhibitor intermediate in the preparation of an anticancer drug, including the EGFR inhibitor described in the embodiment of the first aspect. Because this application utilizes all the technical solutions of the above-mentioned EGFR inhibitor, it at least has all the beneficial effects brought about by the technical solutions of the above-mentioned embodiments.

[0050] Another aspect of the present invention also relates to the use of an EGFR inhibitor intermediate in the preparation of an EGFR inhibitor. The preparation method is described in WO2021208918A1.

[0051] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0053] Figure 1 This is the H NMR spectrum of compound 4 (EGFR inhibitor intermediate) in Example 1. DETAILED DESCRIPTION

[0054] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts are within the scope of the present invention.

[0055] In the embodiments, the term "alkyl" refers to a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, for example, "alkyl having a carbon number of 1-8" refers to an alkyl group containing 1 to 8 carbon atoms. Suitable examples include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH 3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-C H2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH( )2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0056] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0057] Example 1

[0058] An EGFR inhibitor intermediate, the structure of which is as follows:

[0059]

[0060] The method for synthesizing the above-mentioned EGFR inhibitor intermediate comprises the following steps:

[0061]

[0062] Specifically:

[0063] Synthesis of compound 1:

[0064] Ethylene glycol dimethyl ether (100 ml) and 1-methylpyrazole (20.0 g) were added to a three-necked flask, replaced with nitrogen and cooled to -35°C under nitrogen protection, n-butyl lithium (120 ml) was added dropwise, the temperature was controlled at -35°C, and after the addition was complete, the temperature was kept at -35°C for 30 minutes, N-formylmorpholine (33.65 g) was added dropwise, the temperature was controlled at -20°C, and after the addition was complete, the temperature was kept at -20°C for 30 minutes, methoxymethyltriphenylphosphine chloride (100.2 g) was added, the temperature was raised to 25°C and the reaction was carried out for 1 hour, sampling was monitored by LCMS, and the reaction was terminated when the 1-methylpyrazole content was <1%. After the reaction, acetic acid (15 ml) was added dropwise to quench the reaction, and the temperature was controlled at 25°C and stirred for 10 minutes. Water (40 ml) and ethyl acetate (40 ml) were added and stirred for 10 minutes. The mixture was allowed to stand and the upper organic phase was taken. The lower aqueous phase was extracted once with ethyl acetate (40 ml). The organic phases were combined and concentrated under reduced pressure until there was no fraction to obtain viscous compound 1 (30.61 g) with a yield of 91.1%.

[0065] Synthesis of compound 2:

[0066] Acetonitrile (150 ml), compound 1 (30 g), and sulfuric acid (0.6 g) were added to a three-necked flask. After nitrogen replacement and nitrogen protection, compound A (59 g) and sodium triacetoxyborohydride (60.7 g) were added. The temperature was raised to 50°C and refluxed for 7 hours. Samples were taken for LCMS monitoring. The reaction was completed when the content of compound 1 was less than 1%. After the reaction was completed, the temperature was lowered to 25°C and the reaction solution was poured into water (450 ml). Stirred at 25°C for 30 minutes, the reaction mixture was filtered, the filter cake was rinsed with water, and the filter cake was collected and dried to obtain compound 2 (65.6 g) with a yield of 85.2%.

[0067] Synthesis of compound 3:

[0068] 1,4-Dioxane (250 ml), compound 2 (50 g), and potassium acetate (27.6 g) were added to a three-necked flask. The atmosphere was replaced with nitrogen, and tris(dibenzylideneacetone)dipalladium (2 g) was added under nitrogen protection. The temperature was raised to 85°C under nitrogen protection and the reaction was allowed to proceed for 14 hours. Samples were taken and monitored by LCMS. The reaction was completed when the content of compound 2 was less than 0.5%. After the reaction, the temperature was lowered to 25°C, and the reaction solution was poured into water (500 ml). Stirred at 25°C for 30 minutes, the reaction mixture was filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 3 (31.7 g) with a yield of 82.2%.

[0069] Synthesis of compound 4 (EGFR inhibitor intermediate):

[0070] DMF (150 ml) and compound 3 (30 g) were added to a three-necked flask. The mixture was replaced with nitrogen and cooled to 5°C under nitrogen protection. Potassium tert-butoxide (18.4 g) was added and stirred at 5°C for 30 minutes. Isopropyl bromide (20.18 g) was added dropwise at 5°C. After the addition was complete, the temperature was raised to 25°C and the reaction was allowed to proceed for 12 hours. Samples were taken for LCMS monitoring. The reaction was completed when the content of compound 3 was <0.5%. After the reaction was completed, the reaction solution was slowly poured into water (450 ml) precooled to 5°C to quench the reaction. The mixture was stirred at 20°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 4 (EGFR inhibitor intermediate) (31.5 g) with a yield of 90.3%.

[0071] The H NMR spectrum of compound 4 (EGFR inhibitor intermediate) is as follows Figure 1 As shown, specifically, the data is as follows:

[0072] 1 H NMR(500MHz,Chloroform-d)δ8.41(s,1H),7.75(s,1H),,6.50(s,1H),4.02(q,J=6.6Hz,1H), 3.95(s,3H),3.82(s,3H),3.33(t,J=5.2Hz,2H),2.94(t,J=5.3Hz,2H),1.36(d,J=6.6Hz,6H).

[0073] Example 2

[0074] An EGFR inhibitor intermediate, the structure of which is as follows:

[0075]

[0076] The method for synthesizing the above-mentioned EGFR inhibitor intermediate comprises the following steps:

[0077]

[0078] Specifically:

[0079] Synthesis of compound 1:

[0080] Ethylene glycol dimethyl ether (100 ml) and 1-methylpyrazole (20.0 g) were added to a three-necked flask, replaced with nitrogen and cooled to -40°C under nitrogen protection, n-butyl lithium (120 ml) was added dropwise, the temperature was controlled at -40°C, and after the addition was complete, the temperature was kept at -40°C for 30 minutes, N-formylmorpholine (33.65 g) was added dropwise, the temperature was controlled at -25°C, and after the addition was complete, the temperature was kept at -25°C for 30 minutes, methoxymethyltriphenylphosphine chloride (100.2 g) was added, the temperature was raised to 20°C and the reaction was carried out for 1 hour, sampling was monitored by LCMS, and the reaction was terminated when the 1-methylpyrazole content was <1%. After the reaction is completed, acetic acid (15 ml) is added dropwise to quench the reaction, and the temperature is controlled at 20°C and stirred for 10 minutes. Water (40 ml) and ethyl acetate (40 ml) are added and stirred for 10 minutes. The mixture is allowed to stand and the upper organic phase is taken. The lower aqueous phase is extracted once with ethyl acetate (40 ml). The organic phases are combined and concentrated under reduced pressure until there is no fraction to obtain viscous compound 1.

[0081] Synthesis of compound 2:

[0082] To a three-necked flask, acetonitrile (150 ml), compound 1 (30 g), and sulfuric acid (0.6 g) were added. The atmosphere was replaced with nitrogen and then protected with nitrogen. Compound A (59 g) and sodium triacetoxyborohydride (60.7 g) were added. The temperature was raised to 50°C and refluxed for 6 hours. Samples were taken for LCMS monitoring. The reaction was complete when the content of compound 1 was less than 1%. After the reaction was completed, the temperature was lowered to 20°C and the reaction solution was poured into water (450 ml). Stirring was controlled at 20°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 2.

[0083] Synthesis of compound 3:

[0084] To a three-necked flask, 1,4-dioxane (250 ml), compound 2 (50 g), and potassium acetate (27.6 g) were added. The atmosphere was replaced with nitrogen, and tris(dibenzylideneacetone)dipalladium (2 g) was added under nitrogen protection. The temperature was raised to 80°C under nitrogen protection, and the reaction was allowed to proceed for 10 hours. Samples were taken and monitored by LCMS. The reaction was completed when the content of compound 2 was less than 0.5%. After the reaction, the temperature was lowered to 20°C, and the reaction solution was poured into water (500 ml). Stirring was maintained at 20°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 3.

[0085] Synthesis of compound 4 (EGFR inhibitor intermediate):

[0086] DMF (150 ml) and compound 3 (30 g) were added to a three-necked flask. The mixture was replaced with nitrogen and cooled to 0°C under nitrogen protection. Potassium tert-butoxide (18.4 g) was added and stirred at 0°C for 30 minutes. Isopropyl bromide (20.18 g) was added dropwise and the temperature was controlled at 0°C. After the addition was complete, the temperature was raised to 20°C and the reaction was allowed to proceed for 12 hours. The reaction was monitored by LCMS and the reaction was completed when the content of compound 3 was <0.5%. After the reaction was completed, the reaction solution was slowly poured into water (450 ml) precooled to 0°C to quench the reaction. The mixture was stirred at 15°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 4 (EGFR inhibitor intermediate).

[0087] Example 3

[0088] An EGFR inhibitor intermediate, the structure of which is as follows:

[0089]

[0090] The method for synthesizing the above-mentioned EGFR inhibitor intermediate comprises the following steps:

[0091]

[0092] Specifically:

[0093] Synthesis of compound 1:

[0094] Ethylene glycol dimethyl ether (100 ml) and 1-methylpyrazole (20.0 g) were added to a three-necked flask, the atmosphere was replaced with nitrogen and the temperature was lowered to -30°C under nitrogen protection. n-Butyl lithium (120 ml) was added dropwise, the temperature was controlled at -30°C, and the reaction was maintained at -30°C for 30 minutes after the addition was complete. N-formylmorpholine (33.65 g) was added dropwise, the temperature was controlled at -15°C, and the reaction was maintained at -15°C for 30 minutes after the addition was complete. Methoxymethyltriphenylphosphine chloride (100.2 g) was added, the temperature was raised to 30°C, and the reaction was carried out for 1 hour. Sampling was monitored by LCMS. The reaction was terminated when the 1-methylpyrazole content was <1%. After the reaction is completed, acetic acid (15 ml) is added dropwise to quench the reaction, and the temperature is controlled at 30°C and stirred for 10 minutes. Water (40 ml) and ethyl acetate (40 ml) are added and stirred for 10 minutes. The mixture is allowed to stand and the upper organic phase is taken. The lower aqueous phase is extracted once with ethyl acetate (40 ml). The organic phases are combined and concentrated under reduced pressure until there is no fraction to obtain viscous compound 1.

[0095] Synthesis of compound 2:

[0096] To a three-necked flask, acetonitrile (150 ml), compound 1 (30 g), and sulfuric acid (0.6 g) were added. The atmosphere was replaced with nitrogen and then protected with nitrogen. Compound A (59 g) and sodium triacetoxyborohydride (60.7 g) were added. The temperature was raised to 50°C and refluxed for 8 hours. Samples were taken for LCMS monitoring. The reaction was complete when the content of compound 1 was less than 1%. After the reaction, the temperature was lowered to 30°C and the reaction solution was poured into water (450 ml). Stirring was maintained at 30°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 2.

[0097] Synthesis of compound 3:

[0098] To a three-necked flask, 1,4-dioxane (250 ml), compound 2 (50 g), and potassium acetate (27.6 g) were added. The atmosphere was replaced with nitrogen, and tris(dibenzylideneacetone)dipalladium (2 g) was added under nitrogen protection. The temperature was raised to 90°C under nitrogen protection, and the reaction was allowed to proceed for 16 hours. Samples were taken and monitored by LCMS. The reaction was completed when the content of compound 2 was less than 0.5%. After the reaction, the temperature was lowered to 30°C, and the reaction solution was poured into water (500 ml). Stirring was maintained at 30°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 3.

[0099] Synthesis of compound 4 (EGFR inhibitor intermediate):

[0100] DMF (150 ml) and compound 3 (30 g) were added to a three-necked flask. The mixture was replaced with nitrogen and cooled to 10°C under nitrogen protection. Potassium tert-butoxide (18.4 g) was added and stirred at 10°C for 30 minutes. Isopropyl bromide (20.18 g) was added dropwise at 10°C. After the addition was complete, the temperature was raised to 30°C and the reaction was allowed to proceed for 12 hours. Samples were taken for LCMS monitoring. The reaction was completed when the content of compound 3 was <0.5%. After the reaction was completed, the reaction solution was slowly poured into water (450 ml) precooled to 10°C to quench the mixture. The mixture was stirred at 25°C for 30 minutes, filtered, and the filter cake was rinsed with water. The filter cake was collected and dried to obtain compound 4 (EGFR inhibitor intermediate).

[0101] The methods for synthesizing EGFR inhibitor intermediates of Examples 1-3 have at least the following advantages or beneficial effects:

[0102] 1. The existing synthesis method requires 9 steps to obtain the target product, while the method for synthesizing the EGFR inhibitor intermediate of Examples 1-3 only requires 4 steps to obtain the same target product. The method of the present invention has fewer synthesis steps, a simple process and is easy to operate. The entire process does not use dangerous compounds, especially no sodium hydrogen compounds, no palladium carbon catalysts, and no palladium carbon hydrogenation synthesis method, so that the method of the present invention has no safety risks.

[0103] 2. The methods for synthesizing EGFR inhibitor intermediates of Examples 1-3 use readily available starting materials, are low-cost, ensure good reproducibility of the synthetic routes, and are processes that can be scaled up for production.

[0104] The above are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent transformations made using the contents of the present invention specification, or directly or indirectly applied in related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing an EGFR inhibitor intermediate, characterized in that: The following steps are involved: S1 uses compound 0 as the starting material and reacts to obtain compound 1; S2 Compound 1 reacts with compound A to obtain compound 2; S3 Under catalytic conditions, compound 2 reacts to produce compound 3; S4: mixing compound 3 with a bromine-containing compound and reacting the mixture to obtain an EGFR inhibitor intermediate; Among them, the structural formula of compound 0 is: ; Among them, the structural formula of compound 1 is: ; Wherein, the structural formula of compound A is: ; Among them, the structural formula of compound 2 is: ; Among them, the structural formula of compound 3 is: ; Wherein, the EGFR inhibitor intermediate has the following structure: ; wherein R1, R3 and R4 are independently selected from an alkyl group having 1 to 8 carbon atoms. In step S3, the catalytic conditions include using tris(dibenzylideneacetone)dipalladium as a catalyst for the catalytic reaction.

2. The method according to claim 1, wherein: The process of reacting compound 0 to produce compound 1 also includes the following raw materials: a lithium-containing compound, N-formylmorpholine and methoxymethyltriphenylphosphine chloride.

3. The method according to claim 2, wherein: The lithium-containing compound is selected from at least one of n-butyllithium, n-propyllithium and n-ethyllithium.

4. The method according to claim 1, wherein: The catalytic reaction temperature is 80-90°C and the time is 10-16 hours.

5. The method according to claim 1, wherein: Step S4 includes the following steps: mixing compound 3 and a bromine-containing compound under alkaline conditions.

6. The method according to claim 5, characterized in that: The bromine-containing compound is selected from isopropyl bromide.

7. The method according to claim 5, characterized in that: During the mixing process of compound 3 and the bromine-containing compound, the temperature is controlled at 0-10° C. during the mixing, and after the mixing, the temperature is raised to 20-30° C. for reaction.

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